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Inflammopharmacology

, Volume 26, Issue 5, pp 1219–1232 | Cite as

Flavonoid quercetin–methotrexate combination inhibits inflammatory mediators and matrix metalloproteinase expression, providing protection to joints in collagen-induced arthritis

  • Nagaraja Haleagrahara
  • Kelly Hodgson
  • Socorro Miranda-Hernandez
  • Samuel Hughes
  • Anupama Bangra Kulur
  • Natkunam Ketheesan
Original Article

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial tissues in joints, leading to progressive destruction of cartilage and joints. The disease-modifying anti-rheumatic drugs currently in use have side-effects. Thus, there is an urgent need for safe anti-inflammatory therapies for RA. This study aimed to evaluate the therapeutic effect of the flavonoid quercetin on arthritis in mice immunized with type II collagen (CII). An arthritis model was established in C57/BL6 mice by intradermal administration of chicken CII mixed with Freund’s complete adjuvant. Quercetin (30 mg/kg orally) and methotrexate (0.75 mg intraperitoneally twice a week) were administered to investigate their protective effects against collagen-induced arthritis (CIA). Levels of tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and the matrix metalloproteinases (MMP), 3, and 9 were detected to assess the anti-inflammatory effect of quercetin. The mRNA expression of MMP3, MMP9, CCL2, and TNF-α was also measured by quantitative real-time PCR. Quercetin significantly alleviated joint inflammation by reducing the levels of circulating cytokines and MMPs. There was a significant decrease in the expression of TNFα and MMP genes in the ankle joints of arthritic mice. A significant reduction in the levels of knee-joint inflammatory mediators were observed with combined quercetin and methotrexate treatment. Thus, quercetin has the potential to prevent joint inflammation and could be used as an adjunct therapy for RA patients who have an inadequate response to anti-rheumatic monotherapy.

Keywords

Rheumatoid arthritis Flavonoids Inflammation Quercetin Methotrexate 

Notes

Acknowledgements

This study was partially funded by a Grant from AITHM (Faculty Research Grant) and Arthritis Australia Grant 2015 to NH and NK. The Authors would like to thank Dr. Smrithi Krishna for her expert assistance in the gene expression studies.

Authors contribution

NH and NK conceived and designed the study; NH, SMH, KH, SH, and AB performed the research; NH and SMH analysed data; NH, AB, and NK wrote the paper.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.

References

  1. Alam MA, Subhan N, Rahman MM, Uddin SJ, Reza HM, Sarker SD (2014) Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv Nutr 5(4):404–417CrossRefPubMedCentralGoogle Scholar
  2. Brand DD, Kang AH, Rosloniec EF (2003) Immunopathogenesis of collagen arthritis. Springer Semin Immunopathol 25(1):3–18CrossRefGoogle Scholar
  3. Brennan FM, McInnes IB (2008) Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537–3545CrossRefPubMedCentralGoogle Scholar
  4. Brown PM, Pratt AG, Isaacs JD (2016) Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol 12:731–742CrossRefGoogle Scholar
  5. Burda SW, Oleszek W (2001) Antioxidant and antiradical activities of flavonoids. J Agric Food Chem 49:2774–2779CrossRefGoogle Scholar
  6. Campbell IK, Hamilton JA, Wicks IP (2000) Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis. Eur J Immunol 30:1568–1575CrossRefGoogle Scholar
  7. Choi HM, Oh DH, Bang JS, Yang HI, Yoo MC, Kim KS (2010) Differential effect of IL-1beta and TNF alpha on the production of IL-6, IL-8 and PGE2 in fibroblast-like synoviocytes and THP-1 macrophages. Rheumatol Int 30(8):1025–1033CrossRefGoogle Scholar
  8. Choy EH, Panayi GS (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 344(12):907–916CrossRefGoogle Scholar
  9. Clark IM, Rowan AD, Cawston TE (2000) Matrix metalloproteinase inhibitors in the treatment of arthritis. Curr Opin Anti Inflamm Immunomodulat Invest Drugs 2:16–25Google Scholar
  10. Comalada M, Camuesco D, Sierra S, Ballester I, Xaus J, Galvez J (2005) In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. Eur J Immunol 35:584–592CrossRefPubMedCentralGoogle Scholar
  11. Comalada M, Ballester I, Bailón E, Sierra S, Xaus J, Gálvez J, de Medina FS, Zarzuelo A (2006) Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure–activity relationship. Biochem Pharmacol 72:1010–1021CrossRefPubMedCentralGoogle Scholar
  12. Dong C, Yang DD, Wysk M, Whitmarsh AJ, Davis RJ, Flavell RA (1998) Defective T cell differentiation in the absence of Jnk1. Science (New York, NY) 282(5396):2092–2095CrossRefGoogle Scholar
  13. Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397–440CrossRefPubMedCentralGoogle Scholar
  14. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361CrossRefPubMedCentralGoogle Scholar
  15. Gaffen SL (2009) Role of IL-17 in the pathogenesis of rheumatoid arthritis. Curr Rheumatol Rep 11:365–370CrossRefPubMedCentralGoogle Scholar
  16. Gardi C, Bauerova K, Stringa B, Kuncirova V, Slovak L, Ponist S, Drafi F, Bezakova L, Tedesco I, Acquaviva A, Bilotto S, Russo GL (2015) Quercetin reduced inflammation and increased antioxidant defense in rat adjuvant arthritis. Arch Biochem Biophys 583:150–157CrossRefPubMedCentralGoogle Scholar
  17. Goettert M, Schattel V, Koch P, Merfort I, Laufer S (2010) Biological evaluation and structural determinants of p38alpha mitogen-activated-protein kinase and c-Jun-N-terminal kinase 3 inhibition by flavonoids. ChemBioChem Eur J Chem Biol 11(18):2579–2588CrossRefGoogle Scholar
  18. Guardia T, Rotelli AE, Juarez AO, Pelzer LE (2001) Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco 56(9):683–687CrossRefPubMedCentralGoogle Scholar
  19. Haleagrahara N, Radhakrishnan A, Lee N, Kumar P (2009) Flavonoid quercetin protects against swimming stress-induced changes in oxidative biomarkers in the hypothalamus of rats. Eur J Pharmacol 621(1–3):46–52CrossRefPubMedCentralGoogle Scholar
  20. Haraoui B, Pope J (2011) Treatment of early rheumatoid arthritis: concepts in management. Semin Arthritis Rheum 40:371–388CrossRefPubMedCentralGoogle Scholar
  21. Haringman JJ, Smeets TJ, Reinders-Blankert P, Tak PP (2006) Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann Rheum Dis 65(3):294–300CrossRefPubMedCentralGoogle Scholar
  22. Holmdahl R, Bockermann R, Backlund J, Yamada H (2002) The molecular pathogenesis of collagen-induced arthritis in mice—a model for rheumatoid arthritis. Ageing Res Rev 1:135–147CrossRefPubMedCentralGoogle Scholar
  23. Inoue K, Yuasa H (2014) Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet 29(1):12–19CrossRefPubMedCentralGoogle Scholar
  24. Itoh Y (2017) Metalloproteinases in rheumatoid arthritis: potential therapeutic targets to improve current therapies. Prog Mol Biol Transl Sci 148:327–338CrossRefPubMedCentralGoogle Scholar
  25. Iwamoto T, Okamoto H, Toyama Y, Momohara S (2008) Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients. FEBS J 275(18):4448–4455CrossRefPubMedCentralGoogle Scholar
  26. Jackson JK, Higo T, Hunter WL, Burt HM (2006) The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis. Inflamm Res 55(4):168–175CrossRefPubMedCentralGoogle Scholar
  27. Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF (2005) The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology 44(1):61–66CrossRefPubMedCentralGoogle Scholar
  28. Klimiuk PA, Yang H, Goronzy JJ, Weyand CM (1999) Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent. Clin Immunol 90:65–78CrossRefPubMedCentralGoogle Scholar
  29. Kobylińska A, Janas KM (2015) Health-promoting effect of quercetin in human diet. Postepy Hig Med Dosw 69:51–62CrossRefGoogle Scholar
  30. Koeberle A, Laufer SA, Werz O (2016) Design and development of microsomal prostaglandin E2 synthase-1 inhibitors: challenges and future directions. J Med Chem 59(13):5970–5986CrossRefGoogle Scholar
  31. Kojima T, Yabe Y, Kaneko A, Hirano Y, Ishikawa H, Hayashi M et al (2013) Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis. Mod Rheumatol 3(5):977–985CrossRefGoogle Scholar
  32. Kremer JM, Lawrence DA, Hamilton R, McInnes IB (2016) Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures. RMD Open 2(1):e000287CrossRefPubMedCentralGoogle Scholar
  33. Lahiri M, Santosa A, Teoh LK, Clayton JA, Lim SY, Teng GG, Cheung PPM (2017) Use of complementary and alternative medicines is associated with delay to initiation of disease-modifying anti-rheumatic drug therapy in early inflammatory arthritis. Int J Rheum Dis 20(5):567–575CrossRefGoogle Scholar
  34. Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2012) The association between interleukin-6 polymorphisms and rheumatoid arthritis: a meta-analysis. Inflamm Res 61:665–671CrossRefGoogle Scholar
  35. Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S et al (2016) Quercetin, inflammation and immunity. Nutrients 8(3):167CrossRefPubMedCentralGoogle Scholar
  36. Lubberts E (2014) Role of T lymphocytes in the development of rheumatoid arthritis. Implications for treatment. Curr Pharm Des 21:142–146CrossRefGoogle Scholar
  37. Ma J-D, Zhou J-J, Zheng D-H, Chen L-F, Mo Y-Q, Wei X, Yang L-J, Dai L (2014) Serum matrix metalloproteinase-3 as a noninvasive biomarker of histological synovitis for diagnosis of rheumatoid arthritis. Mediators Inflamm 2014:179284CrossRefPubMedCentralGoogle Scholar
  38. Mager DR (2015) Methotrexate. Home Healthc Now 33(3):139–141CrossRefGoogle Scholar
  39. Mahmoud MF, EI Hassan NA, Bassossy HM, Fahmy A (2013) Quercetin protects against diabetes-induced exaggerated vasoconstriction in rats: effect on low grade inflammation. PLoS ONE 8:e63784CrossRefPubMedCentralGoogle Scholar
  40. Mamani-Matsuda M, Kauss T, Al-Kharrat A, Rambert J, Fawaz F, Thiolat D, Moynet D, Coves S, Malvy D, Mossalayi MD (2006) Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators. Biochem Pharmacol 72:1304–1310CrossRefPubMedCentralGoogle Scholar
  41. McInnes IB, O’Dell JR (2010) State-of-the-art: rheumatoid arthritis. Ann Rheum Dis 69:1898–1906CrossRefPubMedCentralGoogle Scholar
  42. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442CrossRefPubMedCentralGoogle Scholar
  43. Moreland LW, Heck LW Jr, Koopman WJ (1997) Biologic agents for treating rheumatoid arthritis: concepts and progress. Arthritis Rheum 40:397–409CrossRefPubMedCentralGoogle Scholar
  44. Mulherin D, Fitzgerald O, Bresnihan B (1996) Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 39:115–124CrossRefPubMedCentralGoogle Scholar
  45. Muller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S (2005) Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol 1:102–110CrossRefGoogle Scholar
  46. Nagatomo F, Fugino NGH, Okiura T, Morimatsu F, Takeda I, Ishihara A (2010) Effects of exposure to hyperbaric oxygen on oxidative stress in rats with type II collagen-induced arthritis. Clin Exp Med 10:7–13CrossRefGoogle Scholar
  47. Nandi P, Kingsley G, Scott D (2008) Disease-modifying antirheumatic drugs other than methotrexate in rheumatoid arthritis and seronegative arthritis. Curr Opin Rheumatol 20:251–256CrossRefGoogle Scholar
  48. Nanki T, Nagasaka K, Hayashida K, Saita Y, Miyasaka N (2001) Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol (Baltimore, Md: 1950) 167(9):5381–5385CrossRefGoogle Scholar
  49. Nurmohamed MT, Dijkmans BA (2005) Efficacy, tolerability and cost effectiveness of disease-modifying antirheumatic drugs and biologic agents in rheumatoid arthritis. Drugs 65(5):661–694CrossRefGoogle Scholar
  50. Okamoto H, Yoshio T, Kaneko H, Yamanaka H (2010) Inhibition of NF-kappa B signalling by fasudil as a potential therapeutic strategy for rheumatoid arthritis. Arthritis Rheum 62:82–92CrossRefPubMedCentralGoogle Scholar
  51. Panchal SK, Poudyal H, Brown L (2012) Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. J Nutr 142(6):1026–1032CrossRefPubMedCentralGoogle Scholar
  52. Paradowska A, Maślińiski W, Grzybowska-Kowalczyk A, Łacki J (2007) The function of interleukin 17 in the pathogenesis of rheumatoid arthritis. Arch Immunol Ther Exp (Warsz) 55:329–334CrossRefGoogle Scholar
  53. Perez-Vizcaino F, Duarte J (2010) Flavonols and cardiovascular disease. Mol Aspects Med 31(6):478–494CrossRefPubMedCentralGoogle Scholar
  54. Rioja I, Bush KA, Buckton JB, Dickson MC, Life PF (2004) Joint cytokine quantification in two rodent arthritis models: kinetics of expression, correlation of mRNA and protein levels and response to prednisolone treatment. Clin Exp Immunol 137(1):65–73CrossRefPubMedCentralGoogle Scholar
  55. Roeleveld DM, van Nieuwenhuijze AE, van den Berg WB, Koenders MI (2013) The Th17 pathway as a therapeutic target in rheumatoid arthritis and other autoimmune and inflammatory disorders. BioDrugs Clin Immunother Biopharm Gene Ther 27(5):439–452Google Scholar
  56. Ross JA, Kasum CM (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22:19–34CrossRefPubMedCentralGoogle Scholar
  57. Rotelli AE, Guardia T, Juarez AO, de la Rocha NE, Pelzer LE (2003) Comparative study of flavonoids in experimental models of inflammation. Pharmacol Res 48:601–606CrossRefPubMedCentralGoogle Scholar
  58. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P et al (2015) The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis 74:480–489CrossRefPubMedCentralGoogle Scholar
  59. Saragusti AC, Ortega MG, Cabrera JL, Estrin DA, Marti MA, Chiabrando GA (2010) Inhibitory effect of quercetin on matrix metalloproteinase 9 activity molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction. Eur J Pharmacol 644(1–3):138–145CrossRefPubMedCentralGoogle Scholar
  60. Sato M, Miyazaki T, Kambe F, Maeda K, Seo H (1997) Quercetin, a bioflavonoid, inhibits the induction of interleukin 8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha in cultured human synovial cells. J Rheumatol 24:1680–1684PubMedPubMedCentralGoogle Scholar
  61. Schett G (2007) Cells of the synovium in rheumatoid arthritis. Osteoclasts. Arthritis Res Ther 9:1–6CrossRefGoogle Scholar
  62. Schett G, Zwerina J, Firestein G (2008) The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 67(7):909–916CrossRefPubMedCentralGoogle Scholar
  63. Scott DL, Wolfe F, Huizinga TWJ (2010) Rheumatoid arthritis. Lancet 376:1094–1108CrossRefPubMedCentralGoogle Scholar
  64. Shadick NA, Cook NR, Karlson EW, Ridker PM, Maher NE, Manson JE, Buring JE, Lee IM (2006) C-reactive protein in the prediction of rheumatoid arthritis in women. Arch Intern Med 166(22):2490–2494CrossRefPubMedCentralGoogle Scholar
  65. Shiozawa S, Tsumiyama K, Yoshida K, Hashiramoto A (2011) Pathogenesis of joint destruction in rheumatoid arthritis. Arch Immunol Ther Exp (Warsz) 59(2):89–95CrossRefGoogle Scholar
  66. Simsek I (2011) TNF inhibitors for rheumatoid arthritis—a year in review. Bull NYU Hosp Jt Dis 69(3):220–224PubMedPubMedCentralGoogle Scholar
  67. Subesinghe S, Scott IC (2015) Key findings from studies of methotrexate tapering and withdrawal in rheumatoid arthritis. Expert Rev Clin Pharmacol 8(6):751–760CrossRefPubMedCentralGoogle Scholar
  68. Sun Y, Yao Y, Ding CZ (2014) A combination of sinomenine and methotrexate reduces joint damage of collagen induced arthritis in rats by modulating osteoclast-related cytokines. Int Immunopharmacol 18(1):135–141CrossRefPubMedCentralGoogle Scholar
  69. Sung MS, Lee EG, Jeon HS, Chae HJ, Park SJ, Lee YC et al (2012) Quercetin inhibits IL-1beta-induced proliferation and production of MMPs, COX-2, and PGE2 by rheumatoid synovial fibroblast. Inflammation 35(4):1585–1594CrossRefPubMedCentralGoogle Scholar
  70. Syggelos SA, Aletras AJ, Smirlaki I, Skandalis SS (2013) Extracellular matrix degradation and tissue remodeling in periprosthetic loosening and osteolysis: focus on matrix metalloproteinases, their endogenous tissue inhibitors, and the proteasome. Biomed Res Int 2013:230805CrossRefPubMedCentralGoogle Scholar
  71. Unemori EN, Hibbs MS, Amento EP (1991) Constitutive expression of a 92-kD gelatinase (type V collagenase) by rheumatoid synovial fibroblasts and its induction in normal human fibroblasts by inflammatory cytokines. J Clin Invest 88:1656–1662CrossRefPubMedCentralGoogle Scholar
  72. van der Kooij SM, Allaart CF, Dijkmans BA, Breedveld FC (2008) Innovative treatment strategies for patients with rheumatoid arthritis. Curr Opin Rheumatol 20(3):287–294CrossRefGoogle Scholar
  73. Veale DJ, Orr C, Fearon U (2017) Cellular and molecular perspectives in rheumatoid arthritis. Semin Immunopathol 39(4):343–354CrossRefGoogle Scholar
  74. Wang X, Yan X, Wang F, Ge F, Li Z (2016) Role of methotrexate chronotherapy in collagen-induced rheumatoid arthritis in rats. Z Rheumatol.  https://doi.org/10.1007/s00393-016-0236-6 CrossRefPubMedPubMedCentralGoogle Scholar
  75. Yang DD, Conze D, Whitmarsh AJ, Barrett T, Davis RJ, Rincon M et al (1998) Differentiation of CD4 + T cells to Th1 cells requires MAP kinase JNK2. Immunity 9(4):575–585CrossRefGoogle Scholar
  76. Ye L, Wen Z, Li Y, Chen B, Yu T, Liu L, Zhang J, Ma Y, Xiao S, Ding L, Li L, Huang Z (2014) Interleukin-10 attenuation of collagen-induced arthritis is associated with suppression of interleukin-17 and retinoid-related orphan receptor γt production in macrophages and repression of classically activated macrophages. Arthritis Res Ther 16:R96CrossRefPubMedCentralGoogle Scholar
  77. Yoshihara Y, Yamada H (2007) Matrix metalloproteinases and cartilage matrix degradation in rheumatoid arthritis. Clin Calcium 17(4):500–508PubMedGoogle Scholar
  78. Yucel-Lindberg T, Olsson T, Kawakami T (2006) Signal pathways involved in the regulation of prostaglandin E synthase-1 in human gingival fibroblasts. Cell Signal 18(12):2131–2142CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018
corrected publication April 2018

Authors and Affiliations

  1. 1.Discipline of Biomedicine, College of Public Health, Medical and Veterinary SciencesJames Cook UniversityTownsvilleAustralia
  2. 2.Australian Institute of Tropical Health and MedicineJames Cook UniversityTownsvilleAustralia
  3. 3.School of Science and TechnologyUniversity of New EnglandArmidaleAustralia

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